Effect of varicella‐zoster virus infection and antiviral treatment on the risk for dementia: A meta‐analysis of observational studies

Abstract Background and purpose: There is increasing evidence to support a role for human herpes viruses in the development of neurodegenerative disorders; however, the association between varicella‐zoster virus (VZV) infection and dementia, and the effect of antiviral therapy on the risk for dementia remain unclear. Methods We searched PubMed, Embase, and the Cochrane Library databases from their dates of inception to May 2023. Odds ratios (ORs) with 95% confidence intervals (CIs) served as indicators of effect sizes in evaluations of the effect of VZV infection and antiviral treatment on dementia risk. Subgroup analyses based on study design, study location, diagnostic criteria of dementia, and VZV subtype classification were also performed. Results A total of 10 studies with 316,846 dementia cases were included in the meta‐analysis. We found that any VZV infection (OR: 1.04, 95% CI: .97–1.12; p = .22), herpes zoster (HZ) (OR: 1.05, 95% CI: .96–1.13; p = .28), or HZ involving the cranial nerves (OR: 1.36, 95% CI: .76–2.43; p  =  .304) was not associated with an increased risk of dementia. The results of subgroup analyses were consistent with these findings. However, patients infected with VZV who received antiviral treatment had a lower OR than untreated patients infected with VZV. Compared to individuals not infected with VZV, antiviral therapy in those infected with VZV was associated with reduced risk for dementia. Conclusion The association between VZV infection and dementia may be masked by antiviral treatment. Further studies with longer follow‐up times that consider the severity of VZV infection and antiviral treatment are needed to clarify the contribution of VZV infection to the risk for dementia.


INTRODUCTION
Primary infection with varicella-zoster virus (VZV) is usually confined to children and is typically characterized by a self-limiting fever and chickenpox (Heininger & Seward, 2006).After the resolution of the primary infection, VZV enters a lifelong latent state in the sensory ganglia (Gershon et al., 2015).Reactivation of latent VZV infection during a decline in cell-mediated immunity causes herpes zoster (HZ), which is characterized by painful unilateral vesicles or blisters with a typical dermatomal distribution (Steiner et al., 2007).The incidence tends to increase with advancing age and rises sharply after the age of 50 years (Yawn & Gilden, 2013).In the context of population aging, HZ has become an important public health problem.
Dementia is a progressive neurodegenerative disease that often manifests as memory deficits and cognitive decline (Livingston et al., 2020).Among individuals >65 years of age, 8.1% are estimated to suffer from dementia, which severely threatens families and societies.
Many efforts have been made over the past decade to identify infectious pathogens that can cause dementia (Ou et al., 2020).Recently, an association between VZV infection and dementia has been suggested.Several cases of cognitive impairment or dementia onset after VZV encephalitis have been reported (Bangen et al., 2010;Grahn et al., 2013).Thus, epidemiological studies have been conducted, but the results have been mixed.In the first such work, HZ ophthalmicus was reported to strongly increase the risk for dementia during a 5-year follow-up period (Tsai et al., 2017).However, a recent systematic review summarized data regarding the association between human herpes virus infections and dementia and reported that VZV infection does not increase the risk for dementia (Warren-Gash et al., 2019).In the time since that review was published, at least 7 studies (Choi et al., 2021;Johannesdottir Schmidt et al., 2022;Lopatko Lindman et al., 2021;Lophatananon et al., 2021;Schnier et al., 2021;Shim et al., 2022;Warren-Gash et al., 2022) with 6 million participants have focused on a possible relationship between VZV infection and dementia.Although most of those studies evaluated the relationship between VZV infection and the dementia risk, a few also examined whether the risk for dementia after VZV infection might be modified by antiviral treatment status.However, the effect of VZV infection and antiviral treatment on the risk for dementia is still unclear.We therefore conducted a metaanalysis to examine this relationship, based on all observational studies published up to May 2023.

Literature search
This meta-analysis adhered to the Preferred Reporting Items of Sys-

Inclusion and exclusion criteria
The eligibility criteria were (1) observational studies (case-control or cohort studies) evaluating the effect of VZV infection or antiviral treatment on the risk for dementia; (2) a focus on VZV infection status; (3) a focus on dementia as the outcome; (4) presentation of multivariateadjusted risk ratios (ORs), relative risks, or hazard ratios with 95% confidence intervals (CIs); and (5) sample size >1000.We excluded articles that were not in English, animal and genetic studies, case reports and series, editorials, correspondence, conference abstracts, and reviews.

Data extraction
Two authors independently extracted first author names, publication years, the countries and settings, and the study designs and periods; they also extracted patient characteristics (ages at baseline, sample sizes, classification of VZV infection type, antiviral treatment, dementia assessment methods, and follow-up durations).Any disagreements were resolved by consultation with a third reviewer.

Outcome assessment
The primary analysis focused on assessing the risk for dementia after VZV infection.In an effort to explain the observed among-study het- VZV infections were divided into three types of classifications: (1) VZV infection: seropositivity or DNA of VZV or VZV manifestation; (2) symptomatic zoster: HZ; (3) symptomatic zoster: HZ involving the cranial nerves.

Quality assessment
Two reviewers independently used the nine-item Newcastle-Ottawa scale to assess study quality (Higgins, 2014).This scale rates the quality of an observational study in three domains: selection (four questions) and comparability (two questions) of the study groups, along with the exposure (case-control) or outcome (cohort) of interest (three questions); all items are scored 0 or 1.The scale assigns a maximum of 9 points; studies with Newcastle-Ottawa scale scores ≥7 were considered high quality.

Statistical analysis
STATA software ver.11.0 (Stata Corporation) was used for all analyses.The I 2 statistic was used to evaluate heterogeneity; I 2 > 50% was considered indicative of significant heterogeneity (Higgins & Thompson, 2002).The data were pooled using the DerSimonian and Laird random effects models to manage study heterogeneity (Higgins et al., 2003).ORs were regarded as approximations of relative risks or hazard ratios because dementia was rare in all study populations.Splitting one study into several estimates allowed substantially more weight to be assigned to that study in the meta-analysis, especially in the random effects model.Thus, if more than three estimates from one study were included, a fixed effects model was employed to generate a pooled OR, which was then used in the meta-analysis.Forest plots were used to display the effect sizes and the pooled results.The Egger test (rather than the Begg test) was used to assess publication bias because the number of included studies was small (Egger et al., 1997;Lau et al., 2006).All statistical tests were two-sided; p-values <.05 were considered indicative of statistical significance.

Search results
The search flow is presented in a PRISMA diagram (Figure 1).After the removal of 185 duplicates, our initial search yielded 1305 studies; a total of 1270 of these studies were excluded after title and abstract screening, and 35 studies underwent full-text review.Three studies that used Korean National Health Insurance Service databases were included in this systematic review because they were conducted by different investigators and differed in their design and inclusion criteria, although there was some overlap of study periods and participants.
Therefore, a sensitivity analysis was performed to assess the influence of each study on heterogeneity, and a summary estimate was obtained by including each of these studies from the same database one at a time.Ultimately, 10 studies (Bae et al., 2021;Chen et al., 2018;Choi et al., 2021;Johannesdottir Schmidt et al., 2022;Lopatko Lindman et al., 2021;Lophatananon et al., 2021;Schnier et al., 2021;Shim et al., 2022;Tsai et al., 2017;Warren-Gash et al., 2022) were included in our analysis.

Characteristics of the included studies
The included studies are summarized in Table 1.All 10 studies were population-based; eight were cohort studies, and two were casecontrol studies.The studies were conducted in Korea (three), Taiwan (two), the United Kingdom (two), and Sweden and Denmark (one).The remaining study was conducted using data from Wales, Germany, Scotland, and Denmark.Among the included studies, eight evaluated the association between HZ and dementia.Two studies explored the relationship between VZV infection and dementia, but they did not classify VZV infection according to subtype.Five studies explored the relationship between antiviral treatment and dementia.The sample size ranged from 3384 to 2543,055, with a total of 3780,218 participants.
The number of dementia cases per study ranged from 81 to 129,662, with an overall total of 316,846.The study quality ranged from seven points (moderate) to nine points (high), with a mean of 8.3 points; thus, the overall quality was sufficient to allow meta-analysis.Tables S1 and   S2 list the Newcastle-Ottawa scale score details.

Primary analysis
The results are summarized in Table 2.We did not find a significant association between VZV infection and dementia incidence (OR: 1.04, 95% CI: .97-1.12; p = .22)(Figure 2).Study heterogeneity was assessed using the I 2 statistic; significant heterogeneity (I 2 = 96.6%)was evident.Evaluation of publication bias using the Egger test (Figure S1) revealed no such bias (Egger test p = .6).The sensitivity analysis showed no substantial change in pooled risk estimates upon the exclusion of any single study.When the studies were grouped according to design, no significant association was found in either case-control studies (OR: 0.99, 95% CI: .82-1.19; p = .88)or cohort studies (OR: 1.06, 95% CI: .98-1.14; p = .15).When the studies were grouped according to location, there was no significant association in studies from Asia (OR: 1.09, 95% CI: 1-1.2; p = .058)or Europe (OR: 0.98, 95% CI: .93-1.04; p = .48).When the studies were grouped according to dementia measurement, no significant association was found in studies using diagnostic codes (OR: 1.1, 95% CI: 1-1.21; p = .054)or in studies using diagnostic codes or a prescription of an anti-dementia drug (OR: 0.97, 95% CI: .9-1.03; p = .326).
In the assessment of the three studies that focused on HZ involving the cranial nerves, there was no significant association between HZ and dementia (OR: 1.36, 95% CI: .76-2.43; p = .304).

Secondary analysis
Three studies examined the effect of antiviral treatment on dementia by comparing treated and untreated patients infected with VZV; the pooled data indicated that patients who received antiviral treatment were less likely to develop dementia than those who did not (OR: 0.74, TA B L E 2 Meta-analysis for studies included in the analysis.95% CI: .68-0.8; p < .001)(Figure 3A).Three other studies evaluated the effect of antiviral treatment on dementia by comparing treated patients infected with VZV and people not infected with VZV; an analysis of the pooled data showed a lower dementia incidence among the former (OR: 0.91, 95% CI: .9−0.93; p < .001)(Figure 3B).

DISCUSSION
In our meta-analysis of 10 population-based studies, VZV infection or HZ was not associated with dementia.The results of subgroup analyses were consistent with this finding.In addition, no increased risk Many studies have explored the relationship between VZV infection and dementia because VZV can directly invade the brain and cause inflammation (Haanpää et al., 1998;Kinno et al., 2015).Previous studies reported viral replication in the cerebral arteries (Gilden et al., 2009;Stenmark et al., 2013).Consistent with those findings, VZV DNA was detected in the cerebrospinal fluid of patients with HZ who lacked central nervous system symptoms (Haanpää et al., 1998).VZV can invade the arterial walls to induce vasculopathy and subsequent dementia (Nagel et al., 2008).Virus reactivation-induced neuroinflammation is potentially involved.Inflammation has important roles in the etiologies of neurodegenerative disorders (Cooper et al., 2023;Zhang & Gao, 2022).One clinical study revealed inflammatory cells in the adventitia and intima of patients with both early and prolonged VZV infections (Nagel, 2014).Cytokines secreted by inflammatory cells may disrupt immune balance in the central nervous system.Previous studies claimed that the peripheral levels of interleukin-6, transforming growth factor-β1, and interleukin-1α were useful early markers of dementia (Anuradha et al., 2022;Su et al., 2019).A meta-analysis revealed that Alzheimer's disease was accompanied by inflammation of both the periphery and the cerebrospinal fluid (Swardfager et al., 2010).
However, we found no significant association between VZV infection and dementia.Considering the significant heterogeneity, we conducted further subgroup analyses.The incidence of dementia increases with age (Livingston et al., 2020).However, subgroup analysis according to age revealed no significant association in any age group.We suspect that the different types of dementia in these studies explain the presence of heterogeneity.Vascular dementia is caused by damage to brain-blood vessels or poor blood flow/oxygen delivery to the brain.A recent meta-analysis of 12 studies showed that VZV infection was significantly associated with cerebrovascular and cardiovascular events (Erskine et al., 2017).Thus, it was possible that in patients infected with VZV, there is a higher risk of vascular dementia than Alzheimer's disease; however, surprisingly, this risk was not further investigated.
Our secondary analysis showed a significant association between treatment with antiviral agents and a lower risk for dementia, based it may thus be the case that an association between VZV infection and dementia is masked by antiviral treatment.Even compared to controls, the incidence of dementia was significantly lower in patients infected with VZV who received antiviral treatment.Several possible mechanisms may explain the decreased risk for dementia with the use of antiviral agents.First, symptomatic HZ infection is treated using antiviral agents that relieve pain, accelerate skin lesion healing, and shorten the duration of virus shedding (Andrei & Snoeck, 2021).If treatment is initiated early, it may be possible to prevent the development of postherpetic neuralgia and other complications (Meyer et al., 2022;Vander Straten et al., 2001).A recent epidemiologic study demonstrated that antiviral therapy lowers the risk for HZ-associated stroke (Kim et al., 2021), which is considered a risk factor for dementia.Second, although symptomatic HZ infection does not indicate an increased risk for dementia, the use of antiviral agents may alleviate subclinical VZV activity.Third, it should be noted that other herpes simplex viruses have been found to be associated with a higher risk for dementia (Cohen et al., 2023).Some antiviral agents used for VZV infection may therefore also be effective against other herpes viruses, such as herpes simplex virus 1.Further studies of the associations among VZV infection, antiviral treatment, and dementia should consider the status of other herpes virus infections.
The main strength of our study is that we performed detailed subgroup analyses according to study region and design, type of dementia, dementia measurement, age at entry, and classifications of VZV infection.Additionally, all studies were original, had high quality, and were adjusted for potential confounders.
However, our work had a few limitations, the most important of which was the small number of studies; this may have affected the results of subgroup analyses.Second, the clinical and statistical heterogeneities of the studies may have affected the robustness of our findings.Third, all studies were from Asia or Europe; the absence of work from the Americas or Africa may have affected the generalizability of our findings.Fourth, the severity of VZV infection may influence the risk for dementia.One of the included studies reported a higher risk in patients with a hospital record of VZV infection than in patients with a record of antiviral prescription.Fifth, our included studies lacked information on the effect of VZV vaccination on dementia risk.However, two larger studies have shown a rapid decline in the dementia rate after VZV vaccination (Eyting et al., 2023;Schnier et al., 2022), suggesting an important role of VZV in the etiology of dementia.

F
Forest plot of the overall risk of dementia in relation to varicella zoster virus (VZV) infection.was apparent in patients with HZ of the cranial nerves.Notably, further analysis demonstrated that antiviral treatment was associated with a decreased risk for dementia.To the best of our knowledge, this is the first study to comprehensively synthesize all available population-based research regarding the relationship among VZV infection, antiviral treatment, and dementia.

F
Forest plot of the risk of dementia in relation to antiviral treatment on patients with varicella zoster virus (VZV) infection: (A) treated versus untreated patients with VZV infection; (B) treated patients with VZV infection versus controls.on a comparison of treated and untreated patients infected with VZV;

Table 2
Characteristics of the included studies.
).When the studies were grouped according to study design, no significant association was observed in either case-control studies (OR: 0.99, 95% CI: .82-1.19;TAB L E 1